Evaluation of safety and tolerability,pharmacokinetics, and pharmacodynamics of BMS-820836 in healthy subjects: a placebo-controlled,ascending single-dose study |
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Authors: | Robert Risinger Zubin Bhagwagar Feng Luo Matthew Cahir Laura Miler Anisha E Mendonza Jeffrey H Meyer Ming Zheng Wendy Hayes |
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Institution: | 1. Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Route 206 and Province Line Road, Lawrenceville, NJ, 08543-5400, USA 2. Exploratory Clinical and Translational Research, Bristol-Myers Squibb, 5 Research Parkway, Mailstop: 2BW-610, Wallingford, CT, 06492, USA 3. Department of Psychiatry, Yale University, New Haven, CT, USA 4. Global Clinical Research, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA 5. Research Imaging Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada 6. Campbell Family Mental Health Research Institute, Research Imaging Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada 7. Mood Disorders Division, Centre for Addiction and Mental Health, and Department of Psychiatry, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada 8. Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Pennington Rocky Hill Road, Pennington, NJ, 08543-5400, USA
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Abstract: | Rationale BMS-820836, a novel triple monoamine reuptake inhibitor, is an experimental monotherapy for sufferers of major depressive disorder who have had an inadequate response to an existing antidepressant treatment. Objectives This study was conducted to evaluate the safety and tolerability, pharmacokinetics (PK), and serotonin transporter (SERT) and dopamine transporter (DAT) occupancy for single doses of BMS-820836 in healthy subjects. Methods Healthy subjects were assigned to seven BMS-820836 dose panels (0.025, 0.1, 0.5, 1, 2, 3, and 5 mg; n?=?8 each), in which subjects were randomly allocated 3:1 to a single BMS-820836 dose or matched placebo. Serial blood samples were collected on Days 1, 2, 3, 4, 7, and 14 to characterize the PK of BMS-820836. Following evaluation of the maximum tolerated dose, SERT occupancy was determined by applying 11C]DASB positron emission tomography (PET) after single-dose BMS-820836 (0.5 or 3 mg; n?=?3 each) and DAT occupancy by applying 11C]PE2I PET after single-dose BMS-820836 (3 mg; n?=?6). Results Single oral doses of BMS-820836 (0.025–3 mg) were generally safe and well tolerated. BMS-820836 had a median T max of 5.0–7.2 h and a mean apparent terminal T 1/2 of 34–57 h. Mean striatal SERT occupancies were 19?±?9 % and 82?±?8 % after single doses of 0.5 and 3 mg BMS-820836, respectively. The mean striatal DAT occupancy was 19?±?9 % after a single 3 mg BMS-820836 dose. Conclusions Single doses of BMS-820836 have meaningful SERT and DAT occupancy and demonstrate an acceptable safety and tolerability profile in healthy control subjects. |
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